A new field of anxiety disorder inquiry has been stimulated by the relatively recent "re-discovery" that carbon dioxide inhalation provokes panic attacks and heightened anxiety in patients suffering from panic disorder. The goals of this proposal are to specifically test the hypothesis that patients with panic disorder are hypersensitive to carbon dioxide and determine the proportion of patients who will experience acute panic during inhalation of 3%, 5%, 7% carbon dioxide. In addition, we wish to study the biological and characterological aspects of patients who are sensitive to CO2, as well as the physiological concomitants of an acute carbon dioxide-induced panic attack. A major aim of this research will be to determine if patients previously shown to be sensitive to CO2 are still vulnerable to CO2 once their spontaneous panic attacks have been blocked by anti-panic medications. Finally, we will also study the effect of room air hyperventilation on patients with panic disorder as a comparison to CO2 challenge. This proposal extends our previous work in several ways including a much larger sample size, use of diagnostic and intervention blind to rate the occurrence of panic attacks, more fine-grained biochemical assessments during the experiment, and construction of CO2 response curves. The study will be conducted on a total of 100 patients with panic disorder and 50 normal volunteers. Each subject will undergo a respiratory challenge procedure in which they are administered varying concentrations of CO2 and also asked to hyperventilate room air to induce alkalosis. During the procedure, arterial blood gas and pH determination are made and blood is also collected for a variety of other measures. Breath by breath spirometry is provided by an on-line computer and a continuous heart rate recording is made. Patients will then be treated with anti-panic medication and, when panic-free for one month, restudied in the respiratory challenge procedure. Our working hypothesis is that patients with panic disorder have abnormal sensitivity to CO2 which leads them to chronically hyperventilate in order to maintain low arterial Pco2. The medullary chemoreceptors and/or locus ceruleus may mediate this CO2 hypersensitivity. Anti-panic drugs raise the threshold to CO2 response and should block CO2 panic attacks and anxiety.